Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma

Abstract

Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.

Figure 1

Summary of study design, including dose-escalation phase and eligibility criteria for the 4 expansion cohorts. IMiD, immunomodulatory drug; PD, progressive disease.

Figure 2

Mean platelet count in all patients treated at the ixazomib MTD of 2.97 mg/m². Thrombocytopenia appeared transient and cyclical, with recovery of platelet count toward baseline in the rest period at the end of each treatment cycle.

Figure 3

Ixazomib treatment duration and response. (A) Number of cycles on therapy and response to treatment in patients achieving stable disease or better; (B) individual patients’ best M-protein response to treatment, by treatment cohort.

Figure 4

Ixazomib pharmacokinetic profiles in cycle 1, according to dose. Mean plasma day 1 (A) and day 15 (B) concentration–time profiles; (C-D) geometric mean (%CV) day 1 and day 15 plasma C_max and AUC_0–168hr. C_max, peak concentration.